Stroke and heart attack kill nearly one million people each year in the U.S. alone. There are currently 5.3 million Americans living with a disability caused by brain injury, the result of an either external physical force or internal causes such as anoxia, stroke/ischemic insult, Alzheimer disease, or epilepsy. These neuropathologies often cause an impairment of cognitive, emotional, and/or physiological functioning in the CMS. It has been known for several years that cerebral ischemic episodes, such as those triggered by stroke or by heart attack, are accompanied by massive release of glutamate and Ca2+ overload. However, experimental treatments targeting Ca2+ homeostasis have not been very successful in reducing the volume or severity of neuronal damage. Accumulating evidence suggests that Zinc (Zn2+) is involved in excitotoxic neuronal death after head trauma, epilepsy, cerebral ischemia and reperfusion. Recently, we demonstrated that ischemia as simulated by oxygen and glucose deprivation caused an increase in Zn2+ concentration in global hippocampal slices. Subsequent reperfusion with standard medium resulted in a further increase in Zn2+ levels. The objective is to understand the role of Zn2+ in neuronal damage by determining the relationships of elevated Zn2+ with Ca2+, and by clarifying the role of Zn2+ in ischemic neuronal injury. The Overall Hypothesis of this proposal is that there is an increase in intracellular Zn2+ during OGD and reperfusion. The Zn2+ elevation could contribute to conventional Ca2+ signals or a Ca2+ overload. Therefore, this Zn2+ accumulation could be the precursor for neuronal damage under these conditions and could be the rightful target of therapeutic development of ischemic stroke. The Specific aims of this project are: (1) To identify Zn2+ signals in conventional Ca2+ signaling during transient ischemia as simulated by oxygen and glucose deprivation (OGD) and reperfusion. (2) To determine the interaction of Zn2+ and Ca2+ signaling during transient ischemia. (3) To determine whether elevated Zn2+ is vital to neuronal cell death in transient ischemia. Understanding the nature of Zn2+ accumulation and preventing the development and consequences of high extracellular and intracellular Zn2+ in the brains of patients who have suffered a stroke or heart attack could permit rapid therapeutic intervention to save vulnerable neurons. [unreadable] [unreadable] [unreadable]